Toxicokinetics is not rocket science

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Toxicokinetics is not rocket science

• Kent R. Olson, MD
• Medical Director, SF Division
• California Poison Control System

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. . . a stepwise approach to complicate simple
kinetics concepts and freak out fellows
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Dr. Barts blackboard fun presents ...
Kinetics for DUMMIES ! 1. Absorption 2.
Distribution 3. Elimination
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Case 1

• Biff says he drank 2 beers
• His serum ethanol 0.28 gm/dL
• Possible Questions
• How big is Biff?
• How big are his beers?
• How honest is Biff about his beers?

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2 beers ? EtOH

• Assume
• Pint-sized 500 mL each
• 6.8 EtOH v/v
• EtOH 0.7 g/mL
• Calculation
• 1000mL x 6.8mL EtOH/100mL beer x 0.7 g/mL
• 47.6 g EtOH

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Absorption
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First-pass effect

• Removal of drug after ingestion, by
• Enzymes in the gut wall
• Uptake by the liver
• Vomiting, AC, WBI, etc
• Ethanol first-pass removal 6-7
• Biffs absorbed dose down to 44.5 g
• (47.6 x 93.5 44.5)

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EtOH FP effect modified by

• Gastric emptying time
• Food
• Medications (eg, Reglan, ranitidine)
• Gender
• Age

• Most rapid and complete EtOH absorption
• older
• female
• empty stomach
• on metoclopramide

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Some drugs w/ high FP effect a.k.a. low
bioavailability

• Propranolol
• Cyclosporine
• Morphine
• Desipramine other TCAs
• Implications
• FP removal can be saturated in an OD
• Greater proportion of drug will reach the
  systemic circulation

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Other absorption issues

• Delayed or altered absorption
• Massive OD
• GI motility altered by drug effect
• Anticholinergics
• Opioids
• Solubility
• Modified-release preparations

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Modified-release preparation
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Tylenol Extended Relief ingestion
Serum APAP level
APAP (mg/L)
Prob. Toxic
Poss. Toxic
hrs
Note co-ingestion of Nyquil plus up to 44 g
Tylenol ER Ref Bizovi K et al J Toxicol Clin
Toxicol 1995 33510
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Volume of Distribution (Vd)

• Where the drug goes
• Vd
• mg/kg / mg/L L/kg
• Total body water 0.7 L/kg or 50 L
• ECF 0.25 L/kg or about 15 L in adult
• Plasma 0.07 L/kg or 5 L
• For EtOH Vd 0.7 L/kg

amount in body
Cp
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Vd for some common drugs

• Large Vd
• camphor
• antidepressants
• digoxin
• opioids
• phencyclidine
• phenothiazines

• Small Vd
• alcohols
• lithium
• phenobarbital
• phenytoin
• salicylate
• valproic acid

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Back to Biffs beers . . .

• How big is Biff?If Vd amount in body, then
  Cp0.7 L/kg x Biff (kg) 44.5
  g 0.28 g/dLand Biff
  22.7 kg (50 lb) ??

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Practice Question

• Boff ingested the contents of his mothers old Rx
  of theophylline
• What is the highest possible serum concentration
  he could achieve?
• Boff weighs 80 kg
• Vd theophylline 0.5 L/kg
• Bottle had 20 pills 300 mg Theo-Dur

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Cp dose / Vd

• Max dose 20 x 300 6000 mg
• Vd 0.5 L/kg x 80 kg 40 L
• Max Cp 6000 mg 150 mg/L
• 40 L

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Try this on your own

• How many vials of Digoxin-Fab would be needed
  to neutralize a digoxin serum concentration of 4
  ng/mL? (assuming equilibrium)
• Vd 6 L/kg
• 50 kg elderly woman
• Each vial binds 0.5 mg digoxin

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Question

• Joe has a serum phenytoin level of 10 mg/L w/
  serum albumin 4.4 gm/dL
• Josette has a serum phenytoin level of 5 mg/L w/
  albumin 2.2 gm/dL
• What do they have in common?

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Protein binding
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C
Cnormal binding
P Pnormal
(1 fu) fu
fu fraction unbound
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5 mg/L
Cnormal binding
2.2 4.4
(1 0.1) 0.1
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5 mg/L
Cnormal binding 9.09 mg/L
0.55
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Some drugs w/ high Pr binding

• Carbamazepine fu 0.2
• Phenytoin 0.1
• Salicylic acid 0.16
• Valproic acid 0.15
• Warfarin 0.03
• Note Pr binding can be saturated in OD,
  resulting in greater free fraction

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Effect of saturated Pr binding
Plasma protein bound drug
Drug in tissues
Free drug
Drug in tissues
Plasma proteins SATURATED
Free drug
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Salicylate increasing Vd with incr. dose
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pH and Vd
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Salicylate is a Weak Acid (pKa 3.5)
TISSUES (pH 6.8)
BLOOD (pH 7.4)
URINE (pH variable)
SH
SH
SH
H S-
H S-
H S-
Acidosis
Alkalosis
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Remember Henderson-Hasselbalch?

• Log
  pKa pH
• OR . . .

protonated species unprotonated species
protonated/unprotonated 10pKa-pH
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Question

• What is the proportion of salicylate in the
  non-ionized (protonated) state compared with the
  ionized (non-protonated) state in urine with
• pH 3.5 ?
• pH 7.5 ?

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Answer

• pH 3.5
• Protonated / nonprotonated 103.5-3.5
• Salicylic acid / salicylate 100 1
• Ratio 11
• pH 7.5
• Protonated / nonprotonated 103.5-7.5
• Salicylic acid / salicylate 10-4
• Ratio 110,000

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Dose was 150 mg IV . . . Vd ?
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Dose was 150 mg IV . . . Vd ?
Cp at t 0 7.5 mg/L
Vd dose / Cp 150 / 7.5 20 L
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Digoxin OD in a child
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Lithium
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Elimination
Can you say haff-life?
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Half-life the time it takes for the Cp to drop
in half
1 half-life
2 half-lives
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No. of half-lives Increment Percent of
maximum 1 50 50 2 25 75 3 12.5 87.5 4 6.
25 93.75 5 3.125 96.875 6 1.5625 98.4375
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Slope the proportion of drug elimination per
unit time (natural log graph)
K slope of
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What is Clearance? (Cl)
VOLUME per unit TIME cleared of the drug
units mL/min or L/hr
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Clearance calculation

• If the reported Cl is 200 mL/min,
• What is the Half-life?
• How much drug is gone after 2 hours?

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They reported the CLEARANCE was really good - -
- 200 mL/min . . .

• But, Cl is expressed in mL/min . . .(NOT mg/min
  or gm/hr or tons/day)
• Total drug elimination depends on drug
  concentration mcg/mL x mL/min mg/min

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Now try again

• Cl is 200 mL/min
• Drug concentration is 1000 ng/mL

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Cl x Cp 200 mL/min x 1000 ng/mL 200,000
ng/min 200 mcg/min 0.2
milligrams/minute !
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What is the relationship between Cl and Vd?
Slope Cl Vd
0.693 Vd
t 1/2
Cl
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First-order kinetics
a.k.a. concentration-dependent kinetics
Elimination is LINEAR when plotted on semi-log
graph
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What happens in OD?

• Saturation of normal routes of elimination ?
  zero-order kinetics

First-order Half-life 1
hour Hours Level 0000 60 0100 30 0200 15 0300
7.5
Zero-order Elim. 30 mg/L/hr Hours Level 0
000 210 0100 180 0200 150 0300 120
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Nonlinear kinetics
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Km x dose rate
Css
Vm dose rate
Vm maximum rate of metabolism
Km Cp at which the rate of metabolism is
½ of maximum
What happens when the dose Vm?
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Other factors affecting elimination rate in OD

• Continued absorption from the GUT
• Combined effect on Cp vs time plot makes it
  appear that half-life prolonged
• Hepatic
• Decreased hepatic blood flow
• Liver damage
• Renal
• Oliguria due to hypotension
• Acute renal failure

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Clearance can be

• Metabolic (ClM)
• Renal (ClR)
• Lungs (ClL)
• etc (Cletc)
• and even hemodialysis (ClHD) and other
  extracorporeal methods
• Total Cl ClM ClR ClL Cletc ClHD

Intrinsic clearance (by the body)
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Extracorporeal removal
ARTERY or VEIN
VEIN
Blood from patient
Return to patient
Hemodialysis
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Question

• What is the hemodialysis clearance of Endital, a
  new (but not very effective) antidepressant?
• Vd 40 L/kg
• Cp 1000 ng/mL
• Cout 340 ng/mL
• Dialysis flow rate 300 mL/min

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Hemodialysis Cl
Cout
Cin
Flow rates 250-350 mL/min (w/catheter) Extracti
on ratio Clearance Flow rate x
Extraction ratio
Cin Cout Cin
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1000 - 340
Extraction ratio
2/3
1000
ClHD flow rate x ER 300 x 2/3 200 mL/min
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Whats the half-life on HD?
0.693 Vd
t 1/2
Cl
0.693 x 40 L/kg x 100 kg / 12 L/hr
231 hours !
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OK, whats really the half-life?
0.693 Vd
t 1/2
Need to use Cltotal not ClHD
Cl
Clintrinsic 1500 mL/min (90 L/hr) Ctotal 90
L/hr 12 L/hr (HD) 102 t1/2 0.693 x 4000 L
/ 102 L/hr 27.2 hours
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Continuous Renal Replacement Therapy
(CVVH)
Cp
Cu
(or vein)
Rate of ultrafiltrate production up to 3
L/hr Clearance
x
Cultrafiltrate
Volume/time of ultrafiltrate
(CVVHD)
(or vein)
Cplasma
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Beckmann U et al JTCT 2001 39393-7
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Estimate for Lithium

• Usual renal Cl 25-35 mL/min
• Hemodialysis adds 100-150 mL/min
• But only for 3-4 hours at a time
• Rebound between dialysis sessions
• CVVH adds 20-35 mL/min
• But can be provided continuously
• Volume cleared 50L/dayvs 36 L/day w/ 4 hours
  of HD
• No rebound